Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report

Abstract

BackgroundProgrammed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors have quickly become standard of care for patients with advanced non-small cell lung cancer and increasing numbers of other cancer types. In this report, we discuss the clinical history, pathological evaluation, and genomic findings in a patient with metastatic lung squamous cell cancer (SCC) who developed severe nivolumab-induced pneumonitis preceding durable clinical remission after three doses of nivolumab.Case presentationA patient with chemotherapy-refractory, metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab treatment, concurrently with onset of a potent antitumor response. Despite discontinuation of nivolumab after three doses and the use of high dose oral corticosteroids for grade 3 pneumonitis, continued tumor response to a complete remission by 3 months was evident by radiographic assessment. At the time of this submission, the patient has remained in clinical remission for 14 months. High PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar macrophages and viable tumor cells in the pneumonitis and recurrent tumor specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome sequencing revealed a very high tumor mutation burden (TMB) corresponding to 95–96 percentile in lung SCC, i.e., 87.4–91.0 and 82.9 mut/Mb, respectively, in pre- and post-nivolumab tumor specimens. Except for one, the 13 functional genomic alterations remained the same in the diagnostic, recurrent, and post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the patient’s immune system against one or more preexisting tumor-associated antigens (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in which an oncogenic promoter -146C>T mutation was detected. Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides.ConclusionsNivolumab could quickly reset and sustain host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC patient. Further mechanistic studies are needed to characterize the effective immune cells and define the HLA-restricted TAA(s) and the specific T cell receptor clones responsible for the potent antitumor effect, with the aim of developing precision immunotherapy with improved effectiveness and safety.

Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non–Small-cell Lung Cancer

“…25 Little is known about which risk factors increase the likelihood of irAEs overall and pneumonitis in particular, and what effect irAEs might have on survival. Case reports have suggested an increased risk of pneumonitis in patients who had previously received TRT 26,27 ; however, the recent PACIFIC trial (a global study to assess the effects of MEDI4736 following concurrent chemoradiation in patients with stage III unresectable non-small cell lung cancer) did not show a…”

Early PD-1 Therapy Discontinuation in Responding Metastatic Cancer Patients

“…Clinical evidence has suggested that patients can experience long-term PFS if the immune checkpoint inhibitor is discontinued due to side effects in response [1,[11][12][13]. Interestingly, a recent neoadjuvant study in the field of NSCLC has shown that 45% of patients show major tumor responses even after a short (4 weeks) PD-1 therapy [16].…”

“…Case reports, patient series, and DOI: 10.1159/000493193 clinical trials have shown that patients whose immune checkpoint inhibitor therapy has been discontinued due to severe side effects can experience prolonged responses without need for further treatment [1,[11][12][13]. A single prospective study has addressed the treatment length of PD-1 agents in non-small-cell lung cancer (NSCLC), randomizing responding patients to either discontinue the PD-1 agent at 1 year or continuing therapy until progression.…”

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis

“…It was reported in up to 4% of all-grade irAEs and 1.5% of high-grade irAEs in clinical trials [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Pneumonitis tended to occur early, at a median time of 4.5 weeks (IQR, 2.75-6.25) in four patients described in three case reports, all of whom were treated with nivolumab (Additional file 4: Table S3) [37,40,42]. The median duration of immune treatment was 4.5 (IQR, 2.75-6.25) cycles, implying that immunotherapy did not stop immediately when pneumonitis occurred.…”